The purpose of this research project is to study the interaction of narcotic drugs with cyclic nucleotides in the striatum and other brain areas and their relationship in the process of tolerance to and dependence on morphine. Preliminary results indicate that morphine affects the cyclic AMP system both in vitro and vivo. We have found that morphine administered in vivo or added in vitro produced stimulation of adenylate cyclase activity. Rats dependent on morphine showed a two-fold increase in the basal activity of adenylate cyclase. The basal activity remained elevated up to 72 hours and returned to control levels at 96 hours after the last morphine injection. Morphine in vitro or in vivo inhibited phosphodiesterase activity only at high substrate concentrations. Kinetic analysis indicates a competitive type of inhibition. Morphine-dependent rats developed tolerance to the inhibitory effect of morphine on phosphodiesterase activity. However, morphine-dependent rats showed inhibition of phosphodiesterase activity during the withdrawal period. In order to clarify the mechanism by which morphine affects cyclic nucleotides, a detailed study of changes in striatal cyclic nucleotides will be carried out. In addition, we propose to study further the involvement of nucleus amygdala and mesolimbic system in the pharmacologic effect and in the process of tolerance to and dependence on morphine. The relationship between changes in levels of cyclic nucleotides and behavioral effects after acute and chronic administration of morphine will be investigated. Attempts will be made to modify these changes by treatment with drugs affecting cyclic nucleotides and by selective lesioning of various parts of the dopaminergic system.